Trials of a promising new treatment for Alzheimer’s will begin within weeks – and it might work for adult-onset diabetes as well.
Mark Pepys of the Royal Free and University College Medical School in London and his colleagues have developed a drug designed to rid the body of amyloid, the clumps of misfolded protein that form in the brain of Alzheimer’s sufferers and in the pancreas of people with diabetes.
The drug has already produced promising results in 19 people with a rare condition called systemic amyloidosis, in which deposits build up in various organs.
“It’s early days,” says Leslie Iversen, a pharmacologist at King’s College London. “But these are very big targets lacking any proper medical treatment. If this works it will be a very significant advance.”
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Vaccine disappointment
The forthcoming trials are especially welcome after the disappointment surrounding the recent abandonment of the trial of an Alzheimer’s vaccine developed by Elan Pharmaceuticals. The idea was to provoke the immune system into destroying the deposits, but the trial was halted after some patients showed signs of inflammation of the nervous system.
The new drug, which has proved remarkably non-toxic in the 19 patients with amyloidosis, is very different. It targets a blood protein called serum amyloid P complement. Pepys had discovered that SAP is always present in amyloid, and seems to play a key role in the formation of deposits. “We showed conclusively that it was a valid target,” says Pepys.
His group then screened 100,000 chemicals to see if any of them could disrupt SAP binding. Having identified a promising small molecule, the researchers then spent around six years developing it.
The result is a drug called CPHPC that binds SAP molecules together, prompting the liver to remove them. “It clears the target protein completely from the blood,” says Pepys. “It’s a pretty clever trick.”
Symptom or cause?
In the tests on people with systemic amyloidosis, the treatment dramatically decreased blood SAP levels. However, it is very difficult to tell in living patients whether amyloid clumps have actually been reduced, Pepys says. Nevertheless, he hopes the strategy will work as a treatment for adult-onset or type II diabetes, by halting build-up of the amyloid deposits in the pancreas that help destroy the insulin-producing islet cells.
The situation is more complicated with Alzheimer’s disease because the drug itself is unlikely to make it to the brain. The hope is that removing any SAP circulating in the blood will be enough to draw the protein away from the brain.
However, there are still researchers who believe that amyloid deposits are not themselves the cause of Alzheimer’s disease. “Even if everything works and the amyloid deposits disappear, I can’t guarantee that would arrest the progression of dementia,” admits Pepys. “It might be that it’s too late by then.”
But he adds that even if brain damage happens well before the deposits are fully formed, his team has preliminary evidence that removing SAP could still be beneficial.
Journal reference: Nature (vol 417, p 254)
